DESCRIPTION: GABAergic inhibition plays an atypical "pro-oscillatory" role in the thalamocortical (TC) system. Unlike most other brain areas, where inhibition checks excessive synchronous activation, in the TC system, inhibition synchronizes and drives rhythmic oscillatory behavior involving the tightly interconnected synaptic circuit comprised of thalamus, nucleus reticularis thalami (NRT), and neocortex. Within this circuit, the GABAergic NRT neurons are pacemakers, synchronizing TC rhythms via their powerful inhibitory connections onto neighboring thalamic neurons. TC oscillations normally occur during slow wave sleep, and pathological variants of these rhythms include the spike wave discharges of Generalized Absence epilepsy, and generalized tonic clonic seizures characteristic of most convulsive forms of epilepsy. In these normal and pathological TC oscillations, the nature of cellular activity is fundamentally dissimilar, and these differences may reflect the added contributions of the neocortex to pathological rhythms. The central hypothesis underlying the research to be conducted in this proposal is that mechanisms involved in determining these distinct patterns of activity in pathological and nonpathological TC oscillations fundamentally depend on the cellular and regional properties of GABAergic inhibition within the TC system. Studies proposed in this application are designed to investigate and test this hypothesis through research centered on 3 specific aims: 1. Characterize inhibitory synaptic activity recorded under normal and pathological conditions in thalamic and NRT neurons; 2. Determine how intrinsic thalamic interneurons contribute to generation of TC rhythms; and 3. Investigate how chronic epilepsy-associated alterations in GABAergic inhibition in the TC system contribute to enhanced seizure susceptibility. Results of this research could provide important insight at cellular, synaptic, and molecular levels into mechanisms critically involved in GABAergic regulation of normal and pathological TC rhythmicity. This provides new directions to exploit in therapeutic intervention to control epileptic TC oscillations, as well as new insight into processes potentially altered in genetic forms of epilepsy involving pathological function of the TC system.